Overview of Cervical Cancer Vaccines

1. Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim Division of Cancer Epidemiology and Genetics National Cancer Institute

2. BACKGROUND

3. Infectious Agents Involved in Cancer Pathogenesis Helicobacter Pylori (5.5%) Stomach Cancer Human Papillomaviruses (5.2%) Cervix Other Ano-Genital Sites Oropharynx/Mouth Hepatitis B/C Viruses (4.9%) Liver Cancer Epstein-Barr Virus (1.0%) Burkitt’s Lymphoma Other Lymphomas (HD/NHL) Nasopharngeal Carcinoma (NPC) HIV & HHV-8 (1.0%) Kaposi’s Sarcoma B-cell NHL Leiomyosarcoma SCC of the Conjunctiva Schistosomiasis (0.3%) Bladder Cancer HTLV-I/II (0.1%) ATLL Liver Flukes (<0.1%) Cholangiocarcinoma

4. % of Cancers Attributable to Infectious Agents(Based on 2002 incidence data) 17.7% (1,900,000 cases) of worldwide incidence of cancer attributed to infection. This figure is higher (27%) in developing nations and lower (8%) in developed nations.

5. The Most Common Cancers in Women IARC slides from Nubia Munoz, Year 2000 IARCIARC slides from Nubia Munoz, Year 2000 IARC

6. Pyramid of DiagnosesUnited States

7. HPV Genotypes Tissue tropism Cutaneous vs. mucosal Cancer association Oncogenic Non-oncogenic Unknown 13 HPV types recognized to be linked to cancer HPV-16 accounts for 50% of tumors

8. Experimental/Animal Evidence in Support of a Causal Link Between HPV and Cervical Cancer HPV E6/E7 proteins are capable of binding and inactivating p53 & pRb. Cancer-associated HPV types better able to do so than low-risk types. Integration of viral genome into host in invasive tumors invariably conserves the E6/E7 coding regions (and disrupts E2). BPV is linked to the development of alimentary tract cancers in cows. CRPV is linked to the development of skin tumors in rabbits.

9. HPV Infection at Baseline Predicts Subsequent Precancer and Cancer Sherman et al. (JNCI, 2003)

10. Portland Results (Khan et al. [WS1-03]) Wednesday evening session (6:45) presentations and discussion of HPV genotyping in clinical management.Wednesday evening session (6:45) presentations and discussion of HPV genotyping in clinical management.

11. VACCINES

12. Two Broad Classes of HPV Vaccines Prophylactic Therapeutic

13. Two Broad Classes of HPV Vaccines Prophylactic Antibody-mediated Rely on IR to structural proteins (L1/L2) Most promising candidate is the VLP-based vaccine Therapeutic

14. Two Broad Classes of HPV Vaccines Prophylactic Antibody-mediated Rely on IR to structural proteins (L1/L2) Most promising candidate is the VLP-based vaccine Therapeutic CMI-mediated Rely on IR to proteins required for maintenance of infection & transformation (E2/E6/E7)

17. HPV Vaccine Development Stages Pre-clinical/Animal Studies Phase I/IIA Safety & Immunogenicity Trials Phase IIB Virological Efficacy Trials (Proof-of-Principle) Phase III Efficacy Studies (Pivotal for Licensure)

18. HPV Vaccine Development Stages Pre-clinical/Animal Studies

19. Evidence that Immunization with VLPs Protects Against Infection: Canine Model

20. HPV Vaccine Development Stages Pre-clinical/Animal Studies Phase I/IIA Safety & Immunogenicity Trials

21. NCI/JHU Phase I HPV Vaccine TrialMean Symptom Incidence for All Vaccine Types and Placebo

23. HPV Vaccine Development Stages Pre-clinical/Animal Studies Phase I/IIA Safety & Immunogenicity Trials Phase IIB Virological Efficacy Trials (Proof-of-Principle)

24. HPV16 L1 VLP Proof of Principle Efficacy Trial (1) Placebo controlled trial of 2392 16-23 year old women given 3 intramuscular doses of HPV16 L1 VLP vaccine with alum adjuvant. Analyzed 1533 women who had been fully vaccinated and who were HPV negative throughout vaccination period. Mean duration of follow-up: 17.4 months.

25. HPV16 L1 VLP Proof of Principle Efficacy Trial (2) Transient HPV16 infection: 27 cases in placebos, 6 in vaccinees. Persistent HPV16 infection: 41 cases in placebos, none in vacinees. Total incident infection (transient + persistent): 68 in placebos, 6 in vaccinees. HPV16 associated cytologic abnormalities: 9 in placebo (mild or moderate), none in vacinees.

26. GSK HPV16/18 L1 VLP Proof of Principle Efficacy Trial Design Placebo controlled trial of 1113 15-25 year old women given 3 intramuscular doses of HPV16/18 L1 VLP vaccine with AS04 adjuvant. Analyzed 1113 (100%) women in an Intent-to-Treat (ITT) analysis, and 721 (65%) who had been fully vaccinated and who were HPV negative throughout vaccination period (ATP cohort). Mean duration of follow-up: 18 months.

27. GSK HPV16/18 L1 VLP Proof of Principle Efficacy Trial ResultsITT Analysis

28. HPV Vaccine Development Stages Pre-clinical/Animal Studies Phase I/IIA Safety/Immunogenicity Trials Phase IIB Virological Efficacy Trials (Proof-of-Principle) Phase III Efficacy Studies (Pivotal for Licensure)

29. Three Ongoing Efforts Merck Pharmaceuticals – Gardasil (HPV-16/18/6/11) – Filling in US end 2005 GlaxoSmithKline Biologicals – Cervarix (HPV-16/18) – Filling in Europe 2006 National Cancer Institute in Costa Rica – (HPV-16/18 Cervarix)

30. HPV Vaccine DevelopmentMany Unanswered Questions How long will protection last?

33. HPV Vaccine DevelopmentMany Unanswered Questions How long will protection last? Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit?

35. HPV Vaccine DevelopmentMany Unanswered Questions How long will protection last? Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit? Will vaccination protect men or reduce transmission by men to their partners?

36. HPV Vaccine DevelopmentMany Unanswered Questions How long will protection last? Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit? Will vaccination protect men or reduce transmission by men to their partners? Who should be vaccinated?

37. HPV Vaccine DevelopmentMany Unanswered Questions How long will protection last? Could an L1-based vaccine have any therapeutic (20 prevention) benefit, and if so would that benefit be non-type-specific? Will vaccination protect men or reduce transmission by men to their partners? Who should be vaccinated? Should vaccine valency be increased? If so, which types should be included?

38. Distribution of HPV Types in Cervical Cancer by Geographical Region

39. HPV Vaccine DevelopmentMany Unanswered Questions How long will protection last? Could an L1-based vaccine have any therapeutic (20 prevention) benefit, and if so would that benefit be non-type-specific? Will vaccination protect men or reduce transmission by men to their partners? Who should be vaccinated? Should vaccine valency be increased? If so, which types should be included? How will an effective vaccine affect the need for cervical cancer screening?

40. Acknowledgements National Cancer Institute: Jay Berzofsky (immunology) Clayton Harro (vaccinology) Martha Hutchinson (cytology) Douglas Lowy (virology) Ligia Pinto (immunology) Mark Schiffman (epidemiology) John Schiller (virology) Mark Sherman (pathology) Diane Solomon (pathology) Sholom Wacholder (statistics)